Chagas disease, caused by Trypanosoma cruzi, causes nearly 50,000 deaths a year in Latin America and is a concern in the United States (US) because of the high prevalence of T. cruzi in wildlife, presence of competent reduviid vectors, high numbers of infected immigrants living in the US, and a recent rise in diagnosis of fatal canine and nonhuman primate cases. Our long-range goal is to understand the risk factors that conspire to allow maintenance of T. cruzi in nature and ultimately its transmission to people. In our previous application we provided data on the natural cycle of T. cruzi in US wildlife, virulence of US T. cruzi isolates to various vertebrate hosts, and the ability of native wildlife to transmit exotic strains. As the next objective in pursuit of our long-range goal, we propose to characterize the pathogenicity and immunological response in laboratory mice and woodrats with US T. cruzi isolates. Our central hypothesis is that US T. cruzi strains will elicit variable immunological responses in experimentally infected laboratory mice and woodrats based on variable virulence, molecular, and biological characteristics and prior infection with other trypanosome species. The rationale behind the proposed study is that Chagas disease is a significant cause of heart disease in Latin America and understanding the infection dynamics and immunological responses caused by US isolates of T. cruzi is an essential part of understanding the risks of Chagas disease for US patients. To test our hypothesis we will pursue three specific aims in this proposed application: 1) Characterize cytokine production profile in mice experimentally inoculated with virulent and avirulent strains of T. cruzi, 2) Determine changes in cytokine production and pathology when mice previously exposed to avirulent strains of T. cruzi are challenged with virulent strains, and 3) Determine if infection with T. neotomae alters the ability of woodrats to serve as competent reservoirs for T. cruzi. Our expectations are that, at the conclusion of the proposed project, we will have elucidated the cytokine response of mice to experimental inoculation with virulent or avirulent T. cruzi isolates. Also, we will have determined if a change in cytokine production is responsible for the previously observed protective nature of infection with avirulent strains of T. cruzi. Furthermore, we will have determined if the high prevalence of T. neotomae in a woodrat population in southern Texas is related to the low prevalence of T. cruzi. These data will increase our understanding of why T. cruzi strains differ in their pathogenicity which may lead to an identification of specific alterations in the immunological response responsible for protection of T. cruzi. These data could result in fewer cases of Chagas disease in the US and Latin America. PUBLIC HEALTH RELEVANCE: This 3-year study will increase our understanding of why T. cruzi strains differ in their pathogenicity which may lead to an identification of specific alterations in the immunological response responsible for protection of T. cruzi. These data could result in fewer cases of Chagas disease in the US and Latin America. This application will also provide biomedical research opportunities for undergraduate, graduate, and veterinary students.